Co-occurrence across time and space of drug- and cannabinoid- exposure and adverse mental health outcomes in the National Survey of Drug Use and Health: combined geotemporospatial and causal inference analysis

Background: Whilst many studies have linked increased drug and cannabis exposure to adverse mental health (MH) outcomes their effects on whole populations and geotemporospatial relationships are not well understood. Methods Ecological cohort study of National Survey of Drug Use and Health (NSDUH) geographically-linked substate-shapefiles 2010–2012 and 2014–2016 supplemented by five-year US American Community Survey. Drugs: cigarettes, alcohol abuse, last-month cannabis use and last-year cocaine use. MH: any mental illness, major depressive illness, serious mental illness and suicidal thinking. Data analysis: two-stage, geotemporospatial, robust generalized linear regression and causal inference methods in R. Results 410,138 NSDUH respondents. Average response rate 76.7%. When drug and sociodemographic variables were combined in geospatial models significant terms including tobacco, alcohol, cannabis exposure and various ethnicities remained in final models for all four major mental health outcomes. Interactive terms including cannabis were related to any mental illness (β-estimate = 1.97 (95%C.I. 1.56–2.37), P \u3c  2.2 × 10− 16), major depressive episode (β-estimate = 2.03 (1.54–2.52), P = 3.6 × 10− 16), serious mental illness (SMI, β-estimate = 2.04 (1.48–2.60), P = 1.0 × 10− 12), suicidal ideation (β-estimate = 1.99 (1.52–2.47), P \u3c  2.2 × 10− 16) and in each case cannabis alone was significantly associated (from β-estimate = − 3.43 (− 4.46 − −2.42), P = 3.4 × 10− 11) with adverse MH outcomes on complex interactive regression surfaces. Geospatial modelling showed a monotonic upward trajectory of SMI which doubled (3.62 to 7.06%) as cannabis use increased. Extrapolated to whole populations cannabis decriminalization (4.26%, (4.18, 4.34%)), Prevalence Ratio (PR) = 1.035(1.034–1.036), attributable fraction in the exposed (AFE) = 3.28%(3.18–3.37%), P \u3c 10− 300) and legalization (4.75% (4.65, 4.84%), PR = 1.155 (1.153–1.158), AFE = 12.91% (12.72–13.10%), P \u3c 10− 300) were associated with increased SMI vs. illegal status (4.26, (4.18–4.33%)). Conclusions Data show all four indices of mental ill-health track cannabis exposure across space and time and are robust to multivariable adjustment for ethnicity, socioeconomics and other drug use. MH deteriorated with cannabis legalization. Cannabis use-MH data are consistent with causal relationships in the forward direction and include dose-response and temporal-sequential relationships. Together with similar international reports and numerous mechanistic studies preventative action to reduce cannabis use is indicated

What are the characteristics of vitamin D metabolism in opioid dependence? An exploratory longitudinal study in Australian primary care

OBJECTIVE: Compare vitamin D levels in opioid dependence and control population and adjust for relevant confounding effects. Nuclear hormone receptors (including the vitamin D receptor) have been shown to be key transducers and regulators of intracellular metabolism and comprise an important site of pathophysiological immune and metabolic dysregulation potentially contributing towards pro-ageing changes observed in opioid-dependent patients (ODPs). DESIGN: Longitudinal prospective comparing ODPs with general medical controls (GMCs). SETTING: Primary care. PARTICIPANTS: Prospective review comparing 1168 ODP (72.5% men) and 415 GMC (51.6% men, p INTERVENTIONS: Nil. Observational study only. PRIMARY AND SECONDARY OUTCOMES: Serum vitamin D levels and relevant biochemical parameters. RESULTS: Vitamin D levels were higher in the ODP (70.35±1.16 and 57.06±1.81 nmol/L, p CONCLUSION: Vitamin D was higher in ODP in both sexes in bivariate, cross-sectional, cas

Broad spectrum epidemiological contribution of cannabis and other substances to the teratological profile of northern New South Wales: Geospatial and causal inference analysis

© 2020, The Author(s). Background: Whilst cannabis commercialization is occurring rapidly guided by highly individualistic public narratives, evidence that all congenital anomalies (CA) increase alongside cannabis use in Canada, a link with 21 CA’s in Hawaii, and rising CA’s in Colorado indicate that transgenerational effects can be significant and impact public health. It was therefore important to study Northern New South Wales (NNSW) where cannabis use is high. Methods: Design: Cohort. 2008–2015. Setting: NNSW and Queensland (QLD), Australia. Participants. Whole populations. Exposures. Tobacco, alcohol, cannabis. Source: National Drug Strategy Household Surveys 2010, 2013. Main Outcomes. CA Rates. NNSW-QLD comparisons. Geospatial and causal regression. Results: Cardiovascular, respiratory and gastrointestinal anomalies rose with falling tobacco and alcohol but rising cannabis use rates across Queensland. Maternal age NNSW-QLD was not different (2008–2015: 4265/22084 v. 96,473/490514 \u3e 35 years/total, Chi.Sq. = 1.687, P = 0.194). A higher rate of NNSW cannabis-related than cannabis-unrelated defects occurred (prevalence ratio (PR) = 2.13, 95%C.I. 1.80–2.52, P = 3.24 × 10− 19). CA’s rose more potently with rising cannabis than with rising tobacco or alcohol use. Exomphalos and gastroschisis had the highest NNSW:QLD PR (6.29(2.94–13.48) and 5.85(3.54–9.67)) and attributable fraction in the exposed (84.11%(65.95–92.58%) and 82.91%(71.75–89.66%), P = 2.83 × 10− 8 and P = 5.62 × 10− 15). In multivariable geospatial models cannabis was significantly linked with cardiovascular (atrial septal defect, ventricular septal defect, tetralogy of Fallot, patent ductus arteriosus), genetic (chromosomal defects, Downs syndrome), gastrointestinal (small intestinal atresia), body wall (gastroschisis, diaphragmatic hernia) and other (hypospadias) (AVTPCDSGDH) CA’s. In linear modelling cannabis use was significantly linked with anal stenosis, congenital hydrocephalus and Turner syndrome (ACT) and was significantly linked in borderline significant models (model P \u3c 0.1) with microtia, microphthalmia, and transposition of the great vessels. At robust and mixed effects inverse probability weighted multivariable regression cannabis was related to 18 defects. 16/17 E-Values in spatial models were \u3e 1.25 ranging up to 5.2 × 1013 making uncontrolled confounding unlikely. Conclusions: These results suggest that population level CA’s react more strongly to small rises in cannabis use than tobacco or alcohol; cardiovascular, chromosomal, body wall and gastrointestinal CA’s rise significantly with small increases in cannabis use; that cannabis is a bivariate correlate of AVTPCDSGDH and ACT anomalies, is robust to adjustment for other substances; and is causal

Cannabis consumption patterns explain the east-west gradient in Canadian neural tube defect incidence: An ecological study

While a known link between prenatal cannabis exposure and anencephaly exists, the relationship of prenatal cannabis exposure with neural tube defects (NTDs) generally has not been defined. Published data from Canada Health and Statistics Canada were used to assess this relationship. Both cannabis use and NTDs were shown to follow an east-west and north-south gradient. Last year cannabis consumption was significantly associated (P \u3c .0001; cannabis use–time interaction P \u3c .0001). These results were confirmed when estimates of termination for anomaly were used. Canada Health population data allowed the calculation of an NTD odds ratio) of 1.27 (95% confidence interval = 1.19-1.37; P \u3c 10−11) for high-risk provinces versus the remainder with an attributable fraction in exposed populations of 16.52% (95% confidence interval = 12.22-20.62). Data show a robust positive statistical association between cannabis consumption as both a qualitative and quantitative variable and NTDs on a background of declining NTD incidence. In the context of multiple mechanistic pathways these strong statistical findings implicate causal mechanisms

Geotemporospatial and causal inferential epidemiological overview and survey of USA cannabis, cannabidiol and cannabinoid genotoxicity expressed in cancer incidence 2003–2017: part 3 – spatiotemporal, multivariable and causal inferential pathfinding and exploratory analyses of prostate and ovarian cancers

Background: The epidemiology of cannabinoid-related cancerogenesis has not been studied with cutting edge epidemiological techniques. Building on earlier bivariate papers in this series we aimed to conduct pathfinding studies to address this gap in two tumours of the reproductive tract, prostate and ovarian cancer. Methods: Age-standardized cancer incidence data for 28 tumour types (including “All (non-skin) Cancer”) was sourced from Centres for Disease Control and National Cancer Institute using SEER*Stat software across US states 2001–2017. Drug exposure was sourced from the nationally representative household survey National Survey of Drug Use and Health conducted annually by the Substance Abuse and Mental Health Services Administration 2003–2017 with response rate 74.1%. Federal seizure data provided cannabinoid concentration data. US Census Bureau provided income and ethnicity data. Inverse probability weighted mixed effects, robust and panel regression together with geospatiotemporal regression analyses were conducted in R. E-Values were also calculated. Results: 19,877 age-standardized cancer rates were returned. Based on these rates and state populations this equated to 51,623,922 cancer cases over an aggregated population 2003–2017 of 124,896,418,350. Inverse probability weighted regressions for prostate and ovarian cancers confirmed causal associations robust to adjustment. Cannabidiol alone was significantly associated with prostate cancer (β-estimate = 1.61, (95%C.I. 0.99, 2.23), P = 3.75 × 10− 7). In a fully adjusted geospatiotemporal model at one spatial and two temporal years lags cannabidiol was significantly independently associated with prostate cancer (β-estimate = 2.08, (1.19, 2.98), P = 5.20 × 10− 6). Cannabidiol alone was positively associated with ovarian cancer incidence in a geospatiotemporal model (β-estimate = 0.36, (0.30, 0.42), P \u3c 2.20 × 10− 16). The cigarette: THC: cannabidiol interaction was significant in a fully adjusted geospatiotemporal model at six years of temporal lag (β-estimate = 1.93, (1.07, 2.78), P = 9.96 × 10− 6). Minimal modelled polynomial E-Values for prostate and ovarian cancer ranged up to 5.59 × 1059 and 1.92 × 10125. Geotemporospatial modelling of these tumours showed that the cannabidiol-carcinogenesis relationship was supra-linear and highly sigmoidal (P = 1.25 × 10− 45 and 12.82 × 10− 52 for linear v. polynomial models). Conclusion: Cannabinoids including THC and cannabidiol are therefore important community carcinogens additive to the effects of tobacco and greatly exceeding those of alcohol. Reproductive tract carcinogenesis necessarily implies genotoxicity and epigenotoxicity of the germ line with transgenerational potential. Pseudoexponential and causal dose-response power functions are demonstrated

Impact of converging sociocultural and substance-related trends on US autism rates: Combined geospatiotemporal and causal inferential analysis

Whilst cannabis is known to be toxic to brain development, it is unknown if it is driving rising US autism rates (ASMR). A longitudinal epidemiological study was conducted using national autism census data from the US Department of Education Individuals with Disabilities Act (IDEA) 1991–2011 and nationally representative drug exposure (cigarettes, alcohol, analgesic, and cocaine abuse, and cannabis use monthly, daily, and in pregnancy) datasets from National Survey of Drug Use and Health and US Census (income and ethnicity) and CDC Wonder population and birth data. Analysis was conducted in R. 266,950 were autistic of a population of 40,119,464 8-year-olds in 1994–2011. At national level after adjustment, daily cannabis use was significantly related to ASMR (β estimate = 4.37 (95%C.I. 4.06, 4.68), P \u3c 2.2 × 10–16) as was first pregnancy trimester cannabis exposure (β estimate = 0.12 (0.08, 0.16), P = 1.7 × 10–12). At state level following adjustment for cannabis, cannabigerol (from β estimate = – 13.77 (– 19.41, 8.13), P = 1.8 × 10–6) and Δ9-tetrahydrocannabinol (from β estimate = 1.96 (0.88–3.04), P = 4 × 10–4) were significant. Geospatial state-level modelling showed exponential relationship between ASMR and Δ9-tetrahydrocannabinol and cannabigerol exposure. Exponential coefficients for the relationship between modelled ASMR and Δ9-tetrahydrocannabinol and cannabigerol exposure were 7.053 (6.39–7.71) and 185.334 (167.88–202.79; both P \u3c 2.0 × 10–7). E-values are an instrument related to the evidence for causality in observational studies. High E-values were noted. Dichotomized legal status was linked with elevated ASMR. Data show cannabis use is associated with ASMR, is powerful enough to affect overall trends, and persists after controlling for other major covariates. Cannabinoids are exponentially associated with ASMR. The cannabis–autism relationship satisfies criteria of causal inference

European epidemiological patterns of cannabis- and substance-related congenital cardiovascular anomalies: Geospatiotemporal and causal inferential study

As prenatal and community cannabis exposures have recently been linked with congenital heart disease (CHD), it was of interest to explore these associations in Europe in a causal framework and space-time context. Congenital anomaly data from Eurocat, drug-use data from the European Monitoring Centre for Drugs and Drug Addiction, and income from the World Bank. Countries with rising daily cannabis use had in general higher congenital anomaly rates over time than those without (time: status interaction: β-Est. = 0.0267, P = 0.0059). At inverse probability-weighted panel regression, cannabis terms were positive and significant for CHD, severe CHD, atrial septal defect, ventricular septal defect, atrioventricular septal defect, patent ductus arteriosus, tetralogy of Fallot, vascular disruptions, double outlet right ventricle, transposition of the great vessels, hypoplastic right heart, and mitral valve anomalies from 1.75 × 10 − 19, 4.20 × 10 − 11, \u3c 2.2 × 10 − 16, \u3c 2.2 × 10 − 16, 1.58 × 10− 12, 4.30 × 10 − 9, 4.36 × 10 − 16, 3.50 × 10 − 8, 5.35 × 10 − 12, \u3c 2.2 × 10 − 16, 5.65 × 10 − 5 and 6.06 × 10 − 10. At spatial regression, terms including cannabis were positive and significant for this same list of anomalies from 0.0038, 1.05 × 10 −10, 0.0215, 8.94 × 10 − 6, 1.23 × 10 − 5, 2.05 × 10 − 5, 1.07 × 10 − 6, 8.77 × 10 − 5, 9.11 × 10 − 6, 0.0001, 3.10 × 10 − 7 and 2.17 × 10 − 7. 92.6 % and 75.2 % of 149 E-value estimates and minimum E-values were in high zone \u3e 9; 100.0% and 98.7 % \u3e 1.25. Data show many congenital cardiac anomalies exhibit strong bivariate relationships with metrics of cannabis exposure. Causal inferential modelling for the twelve anomalies selected demonstrated convincing evidence of robust relationships to cannabis which survived adjustment and fulfilled epidemiological criteria for causal relationships. Space-time regression was similarly confirmatory. Epigenomic pathways constitute viable potential mechanisms. Given exponential genotoxic dose-response effects, careful and astute control of cannabinoid penetration is indicated

Contemporary epidemiology of rising atrial septal defect trends across USA 1991–2016: A combined ecological geospatiotemporal and causal inferential study

© 2020, The Author(s). Background: Cardiovascular anomalies are the largest group of congenital anomalies and the major cause of death in young children, with various data linking rising atrial septal defect incidence (ASDI) with prenatal cannabis exposure. Objectives / Hypotheses. Is cannabis associated with ASDI in USA? Is this relationship causal? Methods: Geospatiotemporal cohort study, 1991–2016. Census populations of adults, babies, congenital anomalies, income and ethnicity. Drug exposure data on cigarettes, alcohol abuse, past month cannabis use, analgesia abuse and cocaine taken from National Survey of Drug Use and Health (78.9% response rate). Cannabinoid concentrations from Drug Enforcement Agency. Inverse probability weighted (ipw) regressions. Analysis conducted in R. Results: ASDI rose nationally three-fold from 27.4 to 82.8 / 10,000 births 1991–2014 during a period when tobacco and alcohol abuse were falling but cannabis was rising. States including Nevada, Kentucky, Mississippi and Tennessee had steeply rising epidemics (Time: Status β-estimate = 10.72 (95%C.I. 8.39–13.05), P \u3c 2.0 × 10 − 16). ASDI was positively related to exposure to cannabis and most cannabinoids. Drug exposure data was near-complete from 2006 thus restricting spatial modelling from 2006 to 2014, N = 282. In geospatial regression models cannabis: alcohol abuse term was significant (β-estimate = 19.44 (9.11, 29.77), P = 2.2 × 10 − 4); no ethnic or income factors survived model reduction. Cannabis legalization was associated with a higher ASDI (Time: Status β-estimate = 0.03 (0.01, 0.05), P = 1.1 × 10 -3). Weighted panel regression interactive terms including cannabis significant (from β-estimate = 1418, (1080.6, 1755.4), P = 7.3 × 10 -15). Robust generalized linear models utilizing inverse probability weighting interactive terms including cannabis appear (from β-estimate = 78.88, (64.38, 93.38), P = 1.1 × 10 -8). Marginal structural models with machine-aided SuperLearning association of ASDI with high v. low cannabis exposure R.R. = 1.32 (1.28, 1.36). Model e-values mostly \u3e 1.5. Conclusions: ASDI is associated with cannabis use, frequency, intensity and legalization in a spatiotemporally significant manner, robust to socioeconomicodemographic adjustment and fulfilled causal criteria, consistent with multiple biological mechanisms and similar reports from Hawaii, Colorado, Canada and Australia. Not only are these results of concern in themselves, but they further imply that our list of the congenital teratology of cannabis is as yet incomplete, and highlight in particular cardiovascular toxicology of prenatal cannabinoid and drug exposure

Epidemiological association of cannabinoid- and drug- exposures and sociodemographic factors with limb reduction defects across USA 1989–2016: A geotemporospatial study

Background: Reports of major limb defects after prenatal cannabis exposure (PCE) in animals and of human populations in Hawaii, Europe and Australia raise the question of whether the increasing use of cannabis in USA might be spatiotemporally associated with limb reduction rates (LRR) across USA. Methods: Congenital anomaly data was from the National Birth Defects Prevention Network, drug use data was taken from the National Survey of Drug Use and Health (NSDUH), cannabinoid concentration was estimated from Federal seizure data and ethnicity and income data were from the US Census bureau. Geotemporospatial analysis was conducted in R. Results: 436 LRR datapoints were obtained. LRR was significantly associated with cannabis use and tetrahydrocannabinol (THC) exposure and demonstrated prominent cannabis-use quintile effects. A sharp increase in LRR occurred from the fourth to fifth quintiles of cannabis exposure (mean ± S.E.M 3.78 ± 0.38 to 6.66 ± 0.56/10,000 live births, P = 5.22 × 10−9). In final lagged geospatial models adjusted for ethnicity and income interactive terms including cannabinoids were highly significant and robust to adjustment. States in which cannabis was not legalized had a lower LRR (4.28 v 5.01/10,000 live births, relative risk reduction = −0.15, (95%C.I. −0.25, −0.02), P = 0.021). Internationally 37–63% of cases are estimated to not be born alive. Their inclusion in these analyzes uniformly intensified the identified effects and the significance of the effect of the cannabis legalization paradigm rose from P = 0.0256 to P = 0.0146 to P = 0.0048 with silent factors of 0%, 36% and 63%, respectively. Conclusion: Therefore a spatiotemporal and dose-dependent association between several cannabinoids including THC and cannabigerol and LRR is reported, is robust to adjustment, is consistent with pathophysiological and preclinical studies, accords with findings elsewhere, is markedly exacerbated in higher exposure quintiles, is exacerbated by cannabis legalization and evidences dose-related intergenerational sequaelae